In mammals, diacylglycerol acyltransferase (DGAT) converts diacylglycerol to triacylglycerol in the final step of the triacylglycerol synthesis pathway. Decreasing triacylglycerol synthesis by inhibiting DGAT1 enzyme activity, therefore, is a strategy to treat obesity and obesity-related complications, dyslipidemia, diabetes, and atherosclerosis.
There are two biochemical pathways for the synthesis of triacylglycerol: the monoacylglycerol pathway, which occurs exclusively in the small intestine (Lehner, R. et al., Prog. Lipid Res., 35:169-201 (1996)), and the glycerol-3-phosphate pathway, which takes place ubiquitously but most notably in the liver and in adipose tissue (Bell, R. M. et al., Annu. Rev. Biochem., 49:459-487 (1980)). The monoacylglycerol pathway initiates from acyl coenzyme A:monoacylglycerol acyltransferase (MOAT) (EC 2.3.1.22). Within minutes of its appearance from the digestion of dietary fat in the lumen of the small intestine, 2-monoacylglycerol is acylated by MGAT to form diacylglycerol. Diacylglycerol is further acylated by acyl coenzyme A:diacylglycerol acyltransferase (DGAT) (EC 2.3.1.20) to re-synthesize triacylglycerol, which is packaged into chylomicron lipoprotein particles that eventually are secreted into the lymph. In the glycerol-3-phosphate pathway, two fatty acyl coenzyme A molecules are added to glycerol-3-phosphate to form phosphatidate. These reactions are followed by the removal of the phosphate group by phosphatidate phosphohydrolase to generate diacylglycerol. Diacylglycerol is then further acylated by DGAT to form triacylglycerol. Collectively, DGAT lies at the final step of both triacylglycerol synthesis pathways.
Two DGAT enzymes have been identified and have been designated as DGAT1 and DGAT2 (Cases, S. et al., Proc. Natl. Acad. Sci. USA, 95:13018-13023 (1998)) (Oelkers, P. et al., J. Biol. Chem., 273:26765-26771 (1998)) (Cases, S. et al., J. Biol. Chem., 276:38870-38876 (2001)). Although they carry out identical enzymatic reactions, DGAT1 and DGAT2 are encoded by two different genes that bear little sequence homology. Functionally, these two enzymes might have different physiological importance in vivo. DGAT1 knockout mice exhibit resistance towards becoming obese when challenged with a high fat (Smith, S. J. et al., Nat. Genet., 25:87-90 (2000)). They are physically more active, possess a higher metabolic rate (Chen, H. C. et al., Trends Cardiovasc. Med., 10:188-192 (2000)) and appear to have greater insulin sensitivity (Chen, H. C. et al., J. Clin. Invest, 109:1049-1055 (2002)). In contrast, DGAT2 knockout mice exhibit phenotypes such as lipopenia and skin barrier abnormalities, resulting in death soon after birth (Stone, S. J. et al., J. Biol. Chem., 279:11767-11776 (2004)).
U.S. Pat. No. 7,300,932 B2 discloses fused bicyclic nitrogen-containing heterocyclic compounds that are useful for treating or preventing conditions and disorders associated with DGAT. As may be appreciated, there still remains a need for new compounds that are inhibitors of DGAT and are useful for the treatment of DGAT related conditions and disorders.
Applicants have found triazolopyridine compounds that have activity as inhibitors of DGAT, in particular DGAT1, and are thereby useful in therapy.